Organophosphate poisoning is caused by exposure to organophosphorus compounds (OPs), which irreversibly inactivate acetylcholinesterase (AChE) by phosphorylating the serine hydroxyl residue on AChE and lead to the accumulation of acetylcholine (ACh) in the body. Such accumulation disrupts cholinergic synaptic transmissions and can lead to various neurotoxic effects, including death in severe cases. OPs are one of the most common causes of poisoning worldwide and are frequently used in suicide attempts. There is an estimated 750,000 to 3 million global cases of OP poisonings per year with hundreds of thousands of annual fatalities (1, 2). Because of their strong toxicity to humans, many OPs are applied in chemical warfare, serving as the primary ingredients in multiple nerve agents including sarin, tabun, soman, and VX. Typically, these nerve agents take effect within 1-10 min of exposure and can cause acute lethality within 15-30 min (3). Combined with their ease of production, highly toxic OPs represent a great threat to both military and civilian populations (4). Effective treatment of OP poisoning is of significant value to public health.
Removal of OPs from the body is difficult because they can easily enter circulation via several routes, including inhalation, ingestion, and dermal absorption. Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs (5), which serve to counteract the effects of excess ACh. Atropine are the most widely used antidote against OP poisoning in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime and obidoxime) for AChE reactivation (6). However, these treatments are associated with serious side effects and can be difficult to administer. Recent meta-analyses indicate that the use of “-oximes” appears to be of no benefit and can potentially be detrimental (7, 8). In addition, it can be difficult to achieve a sufficient level of atropinization (9), as a high dose of the muscarinic antagonist is needed to block the action of over accumulated peripheral ACh following AChE inactivation. Enzyme bioscavengers such as human serum butyrylcholinesterase (BChE) and human paraoxonase 1 (PON1) have been explored as treatment options to react and hydrolyze OPs before they can reach their physiological targets (10-12). However, large-scale production of these recombinant proteins remains a hurdle in their translation (13). Clinical treatment of OP poisoning may thus benefit from alternative strategies that can effectively deactivate the compounds in the bloodstream.
New methods and compositions for decreasing or neutralizing the effect of a toxin, e.g., organophosphate poisoning, in a subject are needed. The present disclosure addresses this and the related needs in the art.